The goal of this proposal is to determine how alterations in mitochondrial metabolism and bioenergetics influence the immunosuppressive phase of sepsis. Sepsis incidence is rising, there are no specific therapies, and most deaths occur during the phase of immunosuppression that follows hyperinflammation. We discovered using a cell-based model of sepsis and human sepsis blood leukocytes that NAD+-dependent deacetylase Sirtuin 1 (Sirt1) activates NF-kB factor RelB to switch proinflammation to immunosuppression, reduce glucose-dependent anabolic pathways and increase catabolic lipolysis and mitochondrial fatty acid oxidation. We also find that Sirt1-activated RelB induces expression of mitochondrial regulator Sirt3, which as a mitochondrial protein promotes catabolic fatty acid oxidation and mitochondrial respiration. Moreover, RelB translocates to mitochondria, binds mitochondrial promoter DNA, and increases transcription of mitochondrial genes. Remarkably, Sirt1 inhibition markedly improves survival of septic mice when administered during the immunosuppressive phase. Substantial data support that switching from anabolism to catabolism can compromise glucose-dependent effector immune responses. Based on these collective data: This proposal will test the hypothesis that protracted Sirt1 activation adversely affects sepsis outcome through a Sirt1-RelB-Sirt3 nuclear-mitochondrial axis (here, called the Sirt1 axis) to decrease net anabolic and increase net catabolic metabolism in myeloid-derived innate immune cells. We have designed 3 aims to explore this new concept: Aim 1: Determine whether Sirt1 axis activation alters mitochondrial metabolism and bioenergetics during sepsis immunosuppression. Aim 2: Determine how mitochondrial gene expression and the electron transport chain are regulated by the Sirt1 axis during the immunosuppressed phase of sepsis. Aim 3: Define how Sirt1 and RelB regulate Sirt3 expression. Approach: Cell-based, murine and human sepsis responses will be investigated using state-of-the art biochemical, molecular cell biology, and genetics tools. Impact: Completing these aims will define the role of the Sirt1 axis in sepsis immunosuppression of innate immunity, identify precise mitochondrial and nuclear processes controlled by the Sirt1 axis, and introduce a new way to treat the disease by rebalancing the net function of the immunometabolic axis.